Lung cancer is a major cause of cancer-related death worldwide, and the prognosis for metastatic NSCLC patients remains poor, with a 5-year survival rate of less than 16%. Our group conducted the first completed, biomarker-driven clinical program titled Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE-1), which incorporated a personalized medicine approach for the treatment of NSCLC; however, resistance to new targeted NSCLC therapies is still an unresolved medical challenge. KRAS is mutated in up to 30% of NSCLC cases and activates multiple signaling pathways that abrogate the effects of many targeted agents being developed for NSCLC; thus, addressing mutant KRAS remains the primary unmet need for NSCLC therapy. We propose to study mechanisms of KRAS signaling and its effects on response to inhibitors of its downstream signaling pathways through our prospective, adaptively randomized trial BATTLE- 2 Program: A Biomarker-Integrated Targeted Therapy Study in Previously Treated Patients with Advanced Non-Small Cell Lung Cancer (BATTLE-2). We will build on knowledge gained from BATTLE-1, including preliminary findings that specific types of KRAS mutation may be correlated with clinical outcome. In BATTLE- 2, patients with refractory NSCLC will undergo a mandated fresh biopsy and, guided by molecular analyses of their tumors, be adaptively randomized to one of 4 arms with an EGFR (erlotinib) or RAF/VEGFR2/PDGFR (sorafenib) inhibitor, or combinations targeting downstream markers of mutant KRAS signaling (erlotinib + AKT inhibitor MK-2206, or MK-2206 + MEK inhibitor AZD-6244). As an adjunct to this clinical study, we will conduct mechanistic studies of KRAS signaling, explore effects of specific types of mutant KRAS, and develop and test a mechanistic KRAS-activated pathway signature in patients' tissue derived from the BATTLE-2 trial. We have annotated clinical data and biopsy samples from BATTLE-1 that fully support the feasibility of this approach and can be used for validation of our discoveries. Specific aims include: 1) To conduct a multi-arm, biopsy- based prospective trial (BATTLE-2) that will test the efficacy of molecularly targeted agents in selected patients with refractory NSCLC, with treatment assignments by a limited (Stage 1) and then refined (Stage 2) adaptive randomization algorithm based on ongoing analyses of tumor molecular markers; 2) To investigate novel mechanisms of mutant KRAS signaling using preclinical NSCLC models; and 3) To develop and test molecular markers/signatures for KRAS-mediated sensitivity and resistance in patient-derived samples from BATTLE-2. Our overall goals are to identify predictive biomarkers of benefit from selected targeted therapies for patients with advanced, refractory NSCLC, discover and elucidate the role of mutant KRAS signaling in NSCLC, and identify new targets and potential therapies that will mitigate the effects of mutant KRAS in NSCLC patients. This overall strategy is a proven approach in our hands and, given the large population of NSCLC patients, will contribute important knowledge and ultimately result in improved outcomes for patients with lung cancer.